The treatment of various diseases using radioisotopes has been of concern for many years with various attempts to have effective treatment to prolong the quality of life of the mammal or human. Various compositions have been tried previously for this purpose with varying degrees of success. Some of these attempts are discussed below.
Bone Cancer
According to the American Academy of Orthopaedic Surgeons, “More than 1.2 million new cancer cases are diagnosed each year [in the US], and approximately 50 percent of these tumors can spread or metastasize to the skeleton.” Metastatic bone cancer therefore afflicts over 500,000 patients in the US alone. Bone is the third most common site of metastatic disease. Cancers most likely to metastasize to bone include breast, lung, prostate, thyroid and kidney. In many cases there are multiple bone metastatic sites making treatment more difficult. Pain, pathological fractures and hypercalcemia are the major source of morbidity associated with bone metastasis. Pain is the most common symptom found in 70% of patients.
Primary bone cancer is much less prevalent (2,370 new cases and 1,330 deaths estimated in the US for 2007), but it is much more aggressive. This type of cancer is more likely to occur in young patients.
In contrast to humans, primary bone cancer is more prevalent in dogs than metastatic bone cancer. Large dogs frequently present with primary bone cancer.
Because of the aggressive nature of the disease, primary bone cancer in humans and animals is often treated by amputation of the area affected to prevent the cancer from spreading. In addition, chemotherapeutic agents are then used to decrease the chance of metastatic disease, especially to the lungs.
The pain associated with bone cancer, especially metastatic bone cancer, is often treated with narcotics. However, the patients have need for increasing amounts of narcotics to control the pain. The deleterious side effects of the narcotics result in a significant decrease in the patient's quality of life.
Another method for treatment is external beam radiation or more recently stereotactic radiotherapy of bone metastatic sites. However, current treatments with high energy electromagnetic radiation do not exclusively deliver radiation to the tumor. This treatment results in the necessity to administer the dose over about a week and has the difficultly of giving high doses of radiation to a tumor without having significant damage resulting to surrounding tissue.
Intraoperative Radiation Therapy (IORT) has permitted localized tumor destruction, but this procedure is expensive and associated with significant trauma due to surgery.
The ability to target bone tumors has been exploited in the field of radiopharmaceuticals for many years. Both diagnostic and therapeutic radiopharmaceuticals capable of targeting bone tumors generally use phosphonic acid functionality as the targeting moiety. For example, pyrophosphates have been used to deliver Tc-99m, a gamma-emitting diagnostic radioisotope, to bone. This technology was displaced by the bisphosphonates because of their increased stability in vivo. In addition, therapeutic radiopharmaceuticals for bone tumors were developed in the 1980's and 1990's. Of these, a series of chelates based on aminomethylene-phosphonic acids offer another type of functionality useful for targeting bone tumors. Thus ethylenediaminetetramethylenephosphonic acid (EDTMP) has been shown to be a very good chelating agent for delivering metals such as Sm, Gd, Ho, and Y to the bone.
Two radiopharmaceuticals, both based on radioactive metals, are marketed in the United States for the treatment of bone metastases. Metastron® (trademark of GE Healthcare Ltd.) is an injectable solution of strontium-89 (Sr-89) given as its chloride salt. Quadramet® (trademark of EUSA Pharma) is a phosphonic acid (EDTMP) chelate of samarium-153 (Sm-153). Both of these agents concentrate in normal bone as well as in the metastatic lesions. This gives a radiation dose to the bone marrow resulting in a temporary but significant suppression of the immune system. For that reason these agents are contraindicated when chemotherapeutic agents are planned as a part of the patient's treatment. Thus a patient may suffer from bone pain while waiting to receive a chemotherapeutic regimen for the primary cancer.
When these available chelates are injected intravenously, about 50% of the injected dose concentrates in the bone. The rest is efficiently cleared by the kidneys and into the bladder; however, because of this clearance, toxicity to these organs has been observed when administering large therapeutic doses of bone seeking radiopharmaceuticals. Although the chelate concentration in the site of a bone tumor is as much as 20 times that of normal bone, significant amounts of radioactivity are taken up by normal bone. In addition, only a small fraction of the radiation dose is associated with the tumor. Because of the fast kidney clearance and uptake in normal bone, only about 0.1% of the dose goes to the site of the tumor. Administration of larger doses of bone agents is limited by the dose to the bone marrow.
An example of the bisphosphonate chelant, methylenediphosphonic acid (MDP), is shown in the structure below.

Two aminomethylenephosphonic acid chelants, ethylenediaminetetra-methylenephosphonic acid (EDTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid) (DOTMP), are shown in the structures below.

To date even combinations of treatments have not been effective at resolving bone tumors. Thus it is still common practice to amputate a limb to stop the spread of bone cancers. In the case of metastatic bone cancer, pain palliation and maintaining quality of life is often the goal in contrast to resolution of the tumors. There clearly is a need for more effective therapy to treat bone cancer.
Stannic (Sn(IV)-117m) chelates have been taught for the palliation of pain from bony metastases and for the treatment and regression of bone cancer by localization of a portion of the radioactive dose in the skeletal system after intravenous injection or infusion. Sn(IV)-117m decays with the emission of abundant conversion electrons of specific energy of 127-129 keV and 152 keV with a half-life of approximately 14 days. These conversion electrons have a range sufficient for irradiating bone tumors, while imparting a smaller dose to the bone marrow versus beta emitting radionuclides. Sn(IV)-117m also possesses an ideal 160 keV gamma emission and can be easily detected and imaged using conventional gamma detectors and thus enables one to monitor the in vivo biodistribution of the isotope.
Srivastava et al. (U.S. Pat. Nos. 4,533,541 and 5,853,695) teach Sn(IV)-117m chelates of methylenediphosphonate (MDP), pyrophosphate (PYP), ethylidenehydroxy disodium phosphonate (EHDP), and diethylenetriaminepentaacetic acid (DTPA) as being capable of localizing in the skeletal system after intravenous injection or infusion.
Srivastava et al. (U.S. Pat. Nos. 6,231,832 and 6,503,477) teach Sn(IV)-117m chelates of polyhydroxycarboxylates, such as oxalates, tartrates, citrates, malonates, gluconates, and glucoheptonates as being capable of localizing in the skeletal system after intravenous injection or infusion.
Srivastava et al. (U.S. Pat. No. 6,004,532) teach the use of the Sn(IV)-117m chelate of DTPA for palliation of bone pain associated with cancer and for the treatment of osseous tumors after intravenous injection or infusion.
Atkins, et al., J. Nucl. Med. 36, 725-729 (1995), and Krishnamurthy, et al., J. Nucl. Med. 38, 230-237 (1997), each report on phase (II) studies using the Sn(IV)-117m DTPA chelate for pain palliation after intravenous injection of the Sn(IV)-117m DTPA formulations.
Srivastava et al., Clin. Cancer Res. 4, 61-68 (1998), report on the use of Sn(IV)-117m DTPA in a phase I/II clinical study for the treatment of metastatic bone pain.
Clearly, there is still a need for a more effective therapy to treat bone pain and bone cancer.
Brachytherapy
In contrast to external beam radiotherapy, where an external beam of radiation is directed to the treatment area, brachytherapy is a form of radiotherapy where a radioactive source is placed inside or next to the area requiring treatment. Conventional brachytherapy is sometimes referred to as sealed source radiotherapy or endocurietherapy and is commonly used to treat localized prostate cancer and cancers of the head and neck. Superficial tumors can be treated by placing sources close to the skin. Interstitial brachytherapy is where the radioactive source is inserted into tissue. Intracavitary brachytherapy involves placing the source in a pre-existing body cavity. Intravascular brachytherapy places a catheter with the source inside blood vessels.
In most of these cases the radioactive material is sealed or encapsulated in a metal casing. Because of this casing, most of the radioactive sources are electromagnetic radiation (i.e., X-rays and gamma photons) emitting radionuclides such that the radiation can penetrate the outer casing and deliver a radiation dose to surrounding tissue. Administration of the radioisotope without this encapsulation may result in migration of the radioisotope to other areas of the body, which may create side effects in the patient. Particle emitting radionuclides such as beta (β) and alpha (α) emitters are rarely used in this method because a significant portion of the dose would not penetrate such metal casing. However, in many instances the gamma photons penetrate beyond the desired treatment area, which results in significant side effects. Therefore, a more specific method to deliver radiation is needed.
The prostate is a gland in the male reproductive system located just below the urinary bladder and in front of the rectum. It is about the size of a walnut and surrounds the urethra. In 2007 the American Cancer Society estimated 218,890 new cases and 27,050 deaths due to prostate cancer in the US. Treatment options include surgery, external radiation therapy, and brachytherapy. In many cases brachytherapy is the preferred choice due to fewer traumas to surrounding tissues. However since the radioisotopes selected for this application are gamma (γ) emitters, the problem of delivering an undesired radiation dose to surrounding tissue remains.
The radioactive sources used for conventional brachytherapy are sealed, for example, in “seeds,” wires, or encapsulated in a metal casing and are referred to as a sealed radioactive source. Conversely, a non-sealed radioactive source is one that is not sealed, for example, in seeds, wires, or encapsulated in a metal casing. Permanent prostate brachytherapy involves implanting between 60 and 120 rice-sized radioactive seeds into the prostate. One type of radioactive seed is based on I-125 which has a 59.4 day half-life and emits multiple X-rays around 30 keV. Recently a shorter half-life alternative has been proposed with Cs-131 which has a 9.7 day half-life and emits X-rays of about 30 keV. Alternatively, Pd-103 is used which has a 17 day half-life and emits X-rays of about 20 keV. Another option is Ir-192 which has a half-life of 73.8 days and gamma emissions at 468 keV. Ir-192 can be used to give different doses to different parts of the prostate. All these isotopes emit electromagnetic radiation that penetrates beyond the prostate and into normal tissue causing problems such as impotence, urinary problems, and bowel problems. Although in most cases the seeds stay in place, seed migration does occur in a portion of patients, usually to the urethra or bladder.
In some cases, brachytherapy is used to destroy cancer cells left over after a surgical procedure. For example, breast cancer patients can be treated with a technology by the name of MammoSite® Radiation Therapy System (trademark of Hologic, Inc.). This involves a balloon catheter that is inserted into the area of the breast where a tumor was removed. The balloon is expanded and radiation is delivered via a small bead attached to a wire. Similarly, the space surrounding a resected brain tumor can be treated using a balloon catheter inflated with a radioactive solution of I-125. This technology is called GliaSite® Radiation Therapy System (e.g., trademark of Cytyc Corp.; U.S. Pat. No. 6,315,979). In these cases the balloon prevents the radioactivity from going systemic. Again, the radioisotopes used are those emitting penetrating electromagnetic radiation (i.e., X-rays or gamma rays).
Beta emitting radioisotopes are being used in what could be categorized as brachytherapy. For example, liver cancer has been treated with a form of brachytherapy. This technology called Selective Internal Radiation Therapy (SIRT) delivers radioactive particles to a tumor via the blood supply. The radioactive particles are positioned via a catheter in the hepatic artery, the portal vein, or a branch of either of these vessels. The catheter is guided to the branch of the blood vessel that feeds the tumor, and then the microspheres are infused. The radioactive microspheres become trapped in the capillary beds of the tumor and the surrounding tissues, which method results in a more targeted radiation dose to the tumor. There are currently two products that take this approach, both are microspheres labeled with Y-90, TheraSphere® (trademark of MDS Nordion, Inc.), and SIR-Spheres® (trademark of SIRTeX® Medical). TheraSpheres are glass microspheres which have a diameter of 25±10 μm so they are trapped mainly within tumor terminal arterioles, which are estimated to have a diameter of 8-10 μm. SIR-Spheres are resin-based microspheres that are approximately 32 μm in diameter. One concern with both of these products is that a portion of the radioactive microspheres can migrate to other tissues such as the lungs and cause undesired side effects.
Ho-166 bound to chitosan has also been proposed to treat cancer cells. Thus J. Nucl. Med. 39(12), 2161-6 (1998 December) describes a method to treat liver cancer by administering this compound via the hepatic artery. However, “shunting” of radioactivity to the lung has again been a problem. In addition, it is a cumbersome technique to determine the blood supply to the tumor and to deliver the particles in the selected blood vessels.
Kyker et al., Federation Proc. 13, 245-246 (1954), Lewin, et al., J. Nat. Cancer Inst. 15, 131-143 (1954), and Andrews et al., International Conference on the Peaceful Uses of Atomic Energy, 10, 122 (1956), describe attempts to treat cancer by forming radioactive colloids in situ in the body but with limited success.
Hyperthermia
Hyperthermia is a procedure where the temperature of a targeted part of the body is raised in order to destroy cancer cells. Usually temperatures in the approximate range of 42-46° C. are employed. Iron oxide magnetic particles have been used to obtain such a temperature range by the action of an externally applied magnetic field. The benefit that the magnetic iron oxide particles bring is that the heating step can be localized at the site of the tumor(s). It has been reported that the “heating potential” of the particles is strongly dependent on the size and shape of the particles so these parameters must be optimized. A particle size in the range of 10 to 50 nm is frequently used. Eileen Gribouski and Rafael Jaimes (The Use of Iron-oxide Nanoparticles for Hyperthermia Cancer Treatment and Simultaneous MRI Monitoring—A major Qualifying Project Submitted to the Faculty Of Worcester Polytechnic Institute, Apr. 30, 2009) have indicated that an effective tumor treatment involves “magnetic embolization hyperthermia” wherein magnetic iron oxide particles are injected directly to the site of treatment. When the particles are exposed to an AC magnetic field, they absorb energy and increase the temperature in the area of the magnetic particles. This technique is effective due to its high selectivity. It has been reported that the hyperthermia process needs to be administered together with other cancer treatments [e.g., Pedro Tartaj et al., “The Preparation of Magnetic Nanoparticles for Applications in Biomedicine,” J. Phys. D: Appl. Phys., 36, R182-R197 (2003)].
Arthritis
Rheumatoid arthritis is a prevalent disease characterized by chronic inflammation of the synovial membrane lining the afflicted joint. It is also classified as an autoimmune disease. Multiple joints are often involved with rheumatoid arthritis. Current treatment methods for severe cases of rheumatoid arthritis include the removal of the synovial membrane, e.g., synovectomy. Surgical synovectomy has many limitations including the risk of the surgical procedure itself and the fact that a surgeon often cannot remove all of the membrane. The diseased tissue remaining may eventually regenerate, causing the same symptoms which the surgery was meant to alleviate.
Radiation synovectomy is radiation-induced ablation of diseased synovial membrane tissue accomplished by injecting a radioactive compound into the diseased synovium. Early attempts to perform radiation synovectomy were hampered by instability of the radioactive compositions utilized and by leakage of such compounds from the synovium into surrounding healthy tissues. The instability of labile radionuclide-complexes resulted in release of the radionuclide from the colloid complex and retention of the radionuclide in surrounding soft tissues. Significant leakage of the radioactive compound from the site of injection exposed normal tissues to dangerous levels or radiation. Because of these limitations, new radiolabeled compositions were sought which would have minimal leakage.
Deutch et al. (WO9105570 A1) teach the use of Re-188 or Re-186 attached to albumin microspheres, sulfur colloids, or glass beads; Simon et al. teach the use of rare earth isotopes such as Sm-153, Ho-166, Y-90, and Lu-177 adsorbed on a previously prepared particle (U.S. Pat. No. 5,300,281); Day et al. (U.S. Pat. No. 4,889,707) teach the use of a biodegradable glass material containing a beta radiation emitting radioisotope; Brodack et al. (U.S. Pat. No. 5,320,824) teach particles that are attached to various radionuclides, and also teach that small colloidal particles of hydroxy apatite can aggregate into non-colloidal particles and have utility for the treatment of arthritis; and Brodack, et al. (WO9701304 A1) teach the use of paramagnetic particles containing therapeutic radionuclides.
Srivastava et al. (U.S. Pat. Nos. 6,231,832 B1 & 6,503,477 B1) teach the use of different Sn(Sn4+)-117m chelates for the treatment of pain resulting from various bone/joint disorders including rheumatoid arthritis and osteoarthritis. Preferred chelating agents include polyhydroxycarboxylates such as oxalates, tartrates, citrates, malonates, gluconates and glucoheptonates.
Liberman et al. (U.S. Pat. No. 4,906,450) teach the use of the radionuclide Sn(II)-121 hydroxide in a carrier of ferric hydroxide macroaggregate. In contrast to Sn(IV)-117m, Sn-121 does not possess gamma photons and is not easily detected and imaged using conventional gamma detectors.
U.S. Pat. Nos. 4,752,464; 4,849,209 and 3,906,450 describe compositions comprising a radioactive colloid in which a radionuclide is entrapped within an iron hydroxide matrix. The radioactive colloids are useful in radiation ablation procedures, for example, ablation of a diseased synovium in rheumatoid arthritis. However, the use of radioactive colloids may still result in significant leakage of radioactivity from the site of injection, e.g., a synovium, and into the surrounding normal tissues, exposing normal tissues to an undesirable amount of radiation. To compensate for the leakage, a radioactive metal having a short half-life, such as dysprosium-165 (Dy-165) with a half-life of 2.3 hours, has been proposed for use as the therapeutic radionuclide. Because of its short half-life, the majority of Dy-165 radioactivity decays before significant leakage can occur, thereby minimizing the dose of radiation to normal tissues.
However, the use of radioactive metals having a short half-life severely limits the utility of the therapeutic radiation procedure in two significant ways. First, radioactive compositions prepared with short half-life isotopes lose a significant amount of radioactivity because of decay during shipment to distant locations. Second, to achieve a therapeutic dose of a composition containing a radioactive metal having a short half-life, large amounts of radioactive materials must be used. As a result, clinical personnel must handle large amounts of radioactive materials, which pose safety issues for repeated exposure to these personnel.
Osteoarthritis is the most common type of arthritis and is caused by the breakdown of joint cartilage. The loss of cartilage and the subsequent bone rubbing on bone is quite painful. Osteoarthritis usually starts in a single joint. Treatment of osteoarthritis focusses on pain relief. Nonsteroidal, anti-inflammatory drugs (NSAIDs), cortisone and hyaluronic acid injections, massage, and other treatments are usually used in an attempt to control the pain. Inflammation in the synovium membrane can be an important factor in individuals with osteoarthritis. Dimitrios Chatzopoulos, et al. [Nuclear Medicine Communications, 30(6), 472-479 (2009)] report that the use of Y-90 synovectomy exerts a beneficial therapeutic effect for a substantial number of patients with osteoarthritis knee pain and synovial inflammation and believe that radiation synovectomy is an option for treating osteoarthritis.
As is evident from the discussion above, better technology to ablate undesirable cells in various diseases is needed. In the general field of brachytherapy and arthritis, more effective methods of delivering radioisotopes to tumors and arthritic sites are needed that give a radiation dose specifically to the treatment area with little to no dose to non-target tissues. Clearly, such an improved technology is desirable to treat these various diseases in humans and animals.